Characterization of the kinetics and mechanisms of inhibition of drugs interacting with the S. cerevisiae multidrug resistance pumps Pdr5p and Snq2p
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't, Validation Study
PubMed
19111673
DOI
10.1016/j.bbamem.2008.12.001
PII: S0005-2736(08)00395-7
Knihovny.cz E-resources
- MeSH
- ATP-Binding Cassette Transporters antagonists & inhibitors chemistry MeSH
- beta-Alanine analogs & derivatives pharmacology MeSH
- Spectrometry, Fluorescence MeSH
- Carbocyanines pharmacology MeSH
- Carbonyl Cyanide m-Chlorophenyl Hydrazone pharmacology MeSH
- Kinetics MeSH
- Saccharomyces cerevisiae Proteins antagonists & inhibitors chemistry MeSH
- Tacrolimus pharmacology MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Validation Study MeSH
- Names of Substances
- 3,3'-dipropylthiacarbocyanine MeSH Browser
- ATP-Binding Cassette Transporters MeSH
- beta-Alanine MeSH
- Carbocyanines MeSH
- Carbonyl Cyanide m-Chlorophenyl Hydrazone MeSH
- PDR5 protein, S cerevisiae MeSH Browser
- Saccharomyces cerevisiae Proteins MeSH
- SNQ2 protein, S cerevisiae MeSH Browser
- Tacrolimus MeSH
- undecyl 3-(dimethylamino)propionate MeSH Browser
We have developed a novel screening method that measures the kinetics and potencies of inhibitors of the yeast multidrug resistance pumps Pdr5p and Snq2p. The assay uses the potentiometric fluorescent probe diS-C(3)(3) (as a benchmark substrate of both pumps) to distinguish drugs with minimal effects on plasma membrane potential as a marker of side-effects on membrane function and integrity. Using FK506, its structural analog rapamycin and enniatin B, we showed that our assay can also be used to determine the minimum drug concentration causing an immediate inhibitory effect and to compare the inhibitory potencies of the drug on the two pumps. We found that the protonophore CCCP effectively inhibits the transport of diS-C(3)(3) by both pumps and confirmed the activation of membrane H(+)-ATPase by CCCP.
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